Platelet-activating factor (PAF) is a potent vasoactive and inflammatory
lipid mediator which has been implicated in the hemodynamic alterations of
endotoxemia and
sepsis. Different PAF receptor antagonists have been shown to attenuate the systemic and pulmonary disturbances of
sepsis, but they were generally administered before the injection of
endotoxin and their effects have not been consistent. To examine the effects of
BB-882, a novel potent PAF receptor antagonist, on general hemodynamics and regional flow distribution in a canine endotoxic
shock model, 14 anesthetized and ventilated dogs received 2 mg/kg of
Escherichia coli endotoxin intravenously (i.v.) followed by generous fluid
resuscitation. Thirty minutes later, the dogs received either
BB-882 (n = 7) as a continuous i.v. infusion with hourly increasing doses (2, 5, and 10 mg/kg.h, respectively) or a corresponding amount of saline (n = 7). The administration of
BB-882 resulted in a dose-dependent reduction in cardiac output and an increase in systemic and pulmonary vascular resistance. Mesenteric and renal flow were not different from control values whereas femoral blood flow progressively decreased. Another group of 7 dogs received 5 mg/kg i.v. bolus of
BB-882 30 min before
endotoxin. Pretreatment significantly increased mesenteric blood flow by about 50% but did not show any significant hemodynamic effects. This study demonstrates that the administration of a PAF receptor antagonist following endotoxic
shock in fluid resuscitated dogs does not offer significant hemodynamic benefit. Pretreatment with
BB-882 at the dose used only enhanced mesenteric perfusion. These findings do not support beneficial effects of PAF receptor antagonists in
septic shock.